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Influence of insulin on growth hormone secretion, level and growth hormone signalling



Growth hormone (GH), as a vital hormone, has to experience a series of processes to fulfill its function including secretion, entering the circulation to reach target tissues (pre-receptor process), binding on the GH receptor (GHR) and triggering signaling inside cells (post-GHR process). Insulin can directly or indirectly influence part of these processes. GH secretion from pituitary somatotropes is regulated by GH-releasing hormone (GHRH) and somatostatin (SS) from hypothalamus. Insulin may exert positive or negative effects on the neurons expressing GHRH and SS and somatotropes under healthy and pathological conditions including obesity and diabetes. Glucose and lipid levels in circulation and dietary habits may influence the effect of insulin on GH secretion. Insulin may also affect GHR sensitivity and the level of insulin-like growth factor 1 (IGF-1), thus influence the level of GH. The GH signaling is also important for GH to play its role. GH signaling involves GHR/JAK2/STATs, GHR/JAK2/SHC/MAPK and GH/insulin receptor substrate (IRS)/PI3K/Akt pathways. These pathways may be shared by insulin, which is the basis for the interaction between insulin and GH, and insulin may attenuate or facilitate the GH signal by influencing molecules in the pathways. Many factors are related to the effect of insulin, among them the most important ones are duration of action and amount of insulin. The tendency of insulin-reduced GH signaling becomes obvious with increased dose and acting time of insulin. The participation of suppressor of cytokine signaling (SOCS), the interaction between JAK2 and IRS, and GHR sensitivity should also be considered when discovering GH signal. The involvement of SS in response to insulin is not clear yet. The details of how GH secretion, level and signaling change in response to time and dose of insulin treatment warrant further studies.
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
DOI: 10.13294/j.aps.2017.0062 541
Influence of insulin on growth hormone secretion, level and growth
hormone signalling
QIU Han1, YANG Jin-Kui2, CHEN Chen3, *
1Department of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; 2Endocrinology
Department, Tongren Hospital, Capital Medical University, Beijing 100730, China; 3School of Biomedical Science, University of
Queensland, Brisbane, Qld 4072, Australia
Abstract: Growth hormone (GH), as a vital hormone, has to experience a series of processes to fulll its function including secretion,
entering the circulation to reach target tissues (pre-receptor process), binding on the GH receptor (GHR) and triggering signaling
inside cells (post-GHR process). Insulin can directly or indirectly inuence part of these processes. GH secretion from pituitary
somatotropes is regulated by GH-releasing hormone (GHRH) and somatostatin (SS) from hypothalamus. Insulin may exert positive or
negative effects on the neurons expressing GHRH and SS and somatotropes under healthy and pathological conditions including
obesity and diabetes. Glucose and lipid levels in circulation and dietary habits may inuence the effect of insulin on GH secretion.
Insulin may also affect GHR sensitivity and the level of insulin-like growth factor 1 (IGF-1), thus inuence the level of GH. The GH
signaling is also important for GH to play its role. GH signaling involves GHR/JAK2/STATs, GHR/JAK2/SHC/MAPK and GH/
insulin receptor substrate (IRS)/PI3K/Akt pathways. These pathways may be shared by insulin, which is the basis for the interaction
between insulin and GH, and insulin may attenuate or facilitate the GH signal by inuencing molecules in the pathways. Many factors
are related to the effect of insulin, among them the most important ones are duration of action and amount of insulin. The tendency
of insulin-reduced GH signaling becomes obvious with increased dose and acting time of insulin. The participation of suppressor
of cytokine signaling (SOCS), the interaction between JAK2 and IRS, and GHR sensitivity should also be considered when discovering
GH signal. The involvement of SS in response to insulin is not clear yet. The details of how GH secretion, level and signaling change
in response to time and dose of insulin treatment warrant further studies.
Key words: insulin; growth hormone; somatostatin; obesity; diabetes; signal pathway
1杨金奎2 3,*
1中山大学中山医学院法医学系,广州 5100802首都医科大学同仁医院内分泌科,北京 1007303昆士兰大学生物医学科学
学院,布里斯班,Qld 4072,澳大利亚
:生长激素(growth hormone, GH)在行使其功能时需要经历一系列的过程,包括从垂体分泌和进入血液循环到达靶器官
或细胞(受体前过程)以及和生长激素受体(GH receptor, GHR)结合并引发细胞内信号转导(受体后过程)。胰岛素可以直接或间
接地影响这些过程。GH从垂体的生长激素分泌细胞中分泌需要依赖于下丘脑释放的生长激素释放激素(GH-releasing hor-
mone, GHRH)和生长激素抑制素(somatostatin, SS),在生理或病理条件下,胰岛素可以对这两种激素以及GH分泌细胞施加不
GHR的敏感性,以及影响胰岛素样生长因子-1 (insulin-like growth factor 1, IGF-1),进而影响GH。受体后过程也是GH行使功
Received 2017-02-20 Accepted 2017-06-10
Research from the corresponding author’s laboratory was partially supported by NHMRC-NSFC and University of Queensland, Australia.
*Corresponding author. Tel: +61-7-33653856; Fax: +61-7-33652398; E-mail:
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
Growth hormone (GH) plays an important role in physical
growth and development by maintaining the normal
structure and functionality of the body through cell
regeneration and protein synthesis [1, 2]. Insulin is a vital
hormone playing a number of roles in the body metab-
olism, especially in the regulation of blood glucose
levels by signaling the liver, muscle and adipose cells
to take in glucose from the blood circulation. As very
important metabolic regulatory hormones, both GH and
insulin work in concert to implement their effects on
the cellular metabolism and biogenic activities. Their
interaction and balance are critical under both patho-
logical and physiological conditions. Understanding the
interaction between GH and insulin is the prerequisite
of understanding the mechanism of many endocrine
processes in maintaining normal metabolic balance, as
well as in metabolic disorders. The effect of GH on in-
sulin, especially on insulin’s sensitivity, has been inten-
sively investigated in past few decades since 1930s [3].
However, given the increasing use of insulin in hor-
mone-replacement therapies to treat diabetes, it is of
great importance and interest to clarify the inuence of
insulin on GH, which is in the process of exploration.
About 50 years ago, Hazelwood and his colleagues
found that diabetes could exert an impact on GH con-
tent inside pituitary gland [4]. In 1978, it was shown that
insulin receptors (IR) were widely distributed in the
central nervous system [5]. Then in 1992, Menon et al.
found that GH-binding protein decreased in children
with type 1 diabetes (T1D) [6]. In 1999, it has been
demonstrated that insulin may inhibit GH signaling [7].
All these studies have indicated complicated actions of
insulin on GH, even though the mechanisms are not
totally understood. To better discuss insulin’s action on
GH, we divide the roles played by GH into two parts:
the pre-receptor process including GH secretion and the
maintenance of GH levels, and the post-GH receptor
(GHR) process which mainly refers to GH signaling.
GH secretion is regulated in a hypothalamus-con-
trolled pattern, which involves the stimulation or inhi-
bition on somatotropes by GH-releasing hormone
(GHRH) or somatostatin (SS) respectively. GH secre-
tion is also inuenced by insulin-like growth factor 1
(IGF-1), which involves negative feedback mechanism.
GH level is greatly determined by GH secretion, but it
is also influenced by insulin to a great extent in both
physiological and pathological conditions. The prole
of plasma GH is related to GH’s functions. The GH
level in circulation changes with a number of factors.
The matters affected by insulin, including GHRH, SS,
IGF-1, the blood glucose and lipid concentration, can
directly or indirectly inuence GH [8–12]. GH signaling
is indispensable for GH to play its part. GH binds with
the GHR, setting up the post-GHR process. The most
essential signal pathways mediated by GHR include
signal transducer and activator of transcription (STAT)
pathway, mitogen-activated protein kinase (MAPK)
pathway and phosphoinositide 3-kinase (PI3K)/Akt
pathway [13]. Previous studies have implied that insulin
may affect GH hormone and downstream signals in a
time- and dose-dependent manner both in vivo and in
vitro, even though there are conicting results under
different experimental conditions [12–15].
1 GH secretion, GH level and GH signalling:
Functioning process of GH
GH, a single-chain polypeptide containing 191 amino
acids, also known as somatotropin, is a hormone that
motivates physical growth and organism development
in human and animals. It also plays an important role in
sustaining the normal structure of the whole body.
Besides the well-known function to facilitate long term
postnatal growth, GH has a vital metabolic regulatory
effect alone or with other hormones on reproduction
and aging (cell reproduction and regeneration), as well
as metabolic processes [2, 16–18].
To function inside the body, GH has to be synthe-
sized, stored, and secreted by somatotropic cells (located
in anterior pituitary gland) by receiving the stimulation
of GHRH from hypothalamus. Then GH goes into the
blood circulation and to distant organs including liver,
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 543
muscles and adipose tissues, to act on all cells possess-
ing GHR [18]. These processes are pre-GHR processes
which involve two fundamental elements: the secretion
of GH and the maintenance of GH level in blood circu-
lation. During these processes, GH can affect and interact
with other hormones, i.e., taking action on pancreatic
islets to regulate insulin and glucagon. Also, it can be
inuenced by other hormones or matters. After GH is
recognized by GHR, it can bind to the receptor, go into
the cell and pass down its signal to motivate a variety
of cellular activities through different signal pathways.
The integrity of GH signal pathways is indispensable
for the transmission of GH signal and implementation
of its function in cell level. This process is the post-
GHR process.
1.1 The secretion of GH
GH secretion is completed and regulated in an axial
pattern. Hypothalamus perceives physiological stimulus
and regulates rhythm of life and releases GHRH, which
is an endogenous hormone. It is also a peptide hormone,
containing 43–44 amino acids. GHRH binds to the
GHRH-receptor of somatotropes in the anterior pituitary
gland. Then, the stored GH inside somatotropes can be
released into circulation and ow through various organs
and cells to implement its function, including going
back to the hypothalamus and pituitary to give feedback.
GHRH is released in a pulsatile way, which leads to the
pulsatile secretion of GH. There is another hormone
existing in the hypothalamus called somatotropin-
releasing inhibitory factor (SRIF, also known as SS or
SST), which is also known as GH- inhibiting hormone
(GHIH) that exists in the digestive organs too, partici-
pating in the secretion of GH[19]. SS is also a peptide
hormone, and it has six different constitutions from
six different genes in zebrash, but humans only pos-
sess one: SS. SS can inhibit GH secretion by inhibiting
the release of GH from somatotropes, thus opposing
the effects of GHRH. SS also has many kinds of recep-
tors exerting different functions besides regulating GH
secretion, such as inhibiting the glucagon to control
glucose in blood [20]. As regulators of GH secretion,
GHRH is more systemic than SS. SS usually plays an
assistant role and works together with other hormones.
GHRH and SS regulate GH secretion together to keep
the normal concentration of GH in circulation [9, 21, 22].
Some hormones or drugs can exert influence on GH
secretion by exerting action on GHRH, SS, and somato-
tropes. Apart from GHRH and SS, GH secretagogue
(GHS) ghrelin also facilitates the secretion of GH. The
axial regulation pattern involves negative feedback
mechanism: GHR exists on pituitary GH cells and
hypothalamus GHRH/SS neurons to receive feedback
and regulate GH release. GH/GHR/IGF-1 axis is another
important axis for regulation of GH secretion which
involves negative feedback mechanism. IGF-1 is
considered GH secretion inhibitor. When IGF-1 gene
was deleted from liver, the level of GHS receptor in
pituitary went up, leading to an improved GH secre-
tion [23]. The GH/IGF-1 system plays a role in the inter-
action among adipose tissue, liver, and pituitary [24].
1.2 GH level in circulation
GH level in blood circulation is essential for normal
metabolism. When the frequency and quantity of GH
pulsatile secretion are influenced, GH concentration
fluctuates. GHR sensitivity also has an effect on GH
level because normal GHR sensitivity is important to
the successful GH utilization. When GHR sensitivity is
impaired, body enhances GH level to make up. GH
prole gives feedback to hypothalamus, the upper head
of axis, thus maintaining a normal concentration. GH/
IGF-1 axis also plays a part in regulating GH level. An
experiment showed that liver-specic deletion of IGF-I
in mice (LI-IGF-I−/−) gave rise to declined circulating
IGF-I and increased plasma GH levels [23].
The prole of plasma GH is correlated to physiologi-
cal and pathological conditions. GH not only acceler-
ates lipolysis, but also regulates glucose metabolism,
and has the ability to enhance blood glucose concentra-
tion. Therefore, diet habits and metabolic diseases can
inuence GH level by changing blood glucose and lipid
content. Non-esterified fatty acid (NEFA) has been
considered a factor to influence GH level, for excess
NEFA restrains GH level [25]. But NEFA and GH level
are not always in inverse proportion to each other. The
regulation of GH level may involve the participation of
insulin. It was found that the GH offsets the effect of
insulin on glucose homoeostasis, so glucose metabo-
lism also accounts for regulating GH level [26, 27]. T1D
patients were found to have a lower insulin level and
higher GH level [28]. This implies that the maintenance
of GH level can be disturbed by other hormones, espe-
cially insulin, which possesses reverse metabolic func-
tions to GH. For the regulation pattern of GH secretion
and GH level, see Fig. 1.
1.3 The signaling of GH
Signalling inside the cell is a post-GHR process, which
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
is the cornerstone for the cellular activities. It is the last
step for GH to function. GH exerts its actions through a
series of signalling pathways and stimulates the phos-
phorylation of groups of molecules. The beginning of
GH signal transmission is the combination of GH to
two GHR molecules. GHR is a member of superfamily
of cytokine/hematopoietic receptors. However, GHR
lacks inherent activity of tyrosine kinase. Fundamentally,
it is connected with a tyrosine-kinase called Janus
kinase (JAK) 2 [29, 30]. After GHR is bound, the
di merization action results in the auto-phosphorylation
of one or more certain tyrosine(s) of JAK2, which
brings a conformational alternation in JAK2 that
changes (decreases or stimulates) JAK2 activity. For
instance, phosphorylation of tyrosine 1 007 has been
considered to expose the ATP or downstream binding
sites, which can also be combined with the negative
regulators of cytokine -- suppressor of cytokine signal-
ing (SOCS), and then stimulates the GHR on tyrosine
residues inside cells [31–33]. Phosphorylated residues on
GHR and JAK2 are docked with a variety of intracellular
transmission intermediators including the STAT family
STAT-1, 3, 5 (including 5a and 5b), and other intracel-
lular substrates including insulin receptor substrate 1
(IRS-1), IRS-2 and src homology and collagen (SHC)
protein [34]. Replenishment of these proteins to the
GHR-JAK2 complexes permits GH to execute a variety
of physiological function [32]. The removal of tyrosine
phosphatises in GHR-JAK2 complex draws the signal
of GH to the end [30, 35]. Among various kinds of cellular
activities, transcription of genes is the most important
one. Three major signal pathways are of great signicance
in this post-GHR process: GHR/JAK2/STATs, GHR/
JAK2/SHC/MAPK and GH/IRS/PI3K/Akt pathways [29].
STAT family contains many subtypes, and the close
relationship between GHR and STAT5b has been
Fig. 1. The physical regulation pattern of GH proles. GH secretion is completed and regulated in an axial pattern. GH is synthesized,
stored, and secreted by somatotropic cells (located in anterior pituitary gland) by receiving the stimulation of GHRH from hypothala-
mus. Meanwhile, GH in pituitary is regulated by somatostatin existing in the hypothalamus, which can be stimulated by insulin from
pancreatic islets and inhibit GH secretion. Insulin can also bind to the insulin receptor (IR) on somatotropes in pituitary and inhibit
GH secretion. An excessive high level of GH in circulation gives negative feedback to hypothalamus and pituitary gland, preventing
GH secretion. GH/GHR/IGF-1 axis is another important axis for regulation of GH secretion, which participates in controlling GH lev-
el in circulation. GH goes to distance organs including liver, muscles, bones and adipose tissues and begins to take action on all cells
possessing GHR. Abbreviations: −, inhibition; +, stimulation; GH, growth hormone; GHR, growth hormone receptor; GHRH, growth
hormone releasing hormone; IGF-1, insulin-like growth factor-1.
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 545
discovered, although STAT5a also plays a role in GH
signal [36–38]. STAT5b is sensitive to pulsatile secretion
of GH [39]. GH-induced tyrosine phosphorylation of
STAT5B is followed by the relocation of cytoplasmic
STAT5 proteins complex to the nuclear area and medi-
ated by an SH2 domain-phosphorylated tyrosine action.
Then target genes’ transcription is motivated, mainly
including c-fos, serine protease inhibitor (spi 2.1), and
SOCS, which are related to somatic growth and devel-
opment and metabolic functions of GH [30, 40–42]. The
growth effect of GH on muscle relies on STAT5b:
muscle IGF-1 transcript and muscle mass weaken due
to the muscle-specic deletion of STAT5B [43]. In
humans, clinical research showed that growth failure
and disorders were related to STAT5b mutation, implying
an irreplaceable post of STAT5b in GH signalling [44–46].
SOCSs are in the downstream pathway of STAT5, and
GH induces four molecules in them, including SOCS-
1, 2, 3 and CIS. The SOCSs family is involved in atten-
uating the GH-induced stimulation of JAK2. Each of
them can block the auto-phosphorylation of JAK2 by
competing for the binding sites in GHR with STATs [47–49].
The Ras-MAPK pathway is also crucial in GH
signalling. In most cases, GH activates GHR/JAK2/
SHC/MAPK pathway by JAK2 phosphorylation of the
protein SHC [50, 51]. Noticeably, IRS-1 is shown to be
involved in this pathway and plays a positive role by
facilitating GH-induced cell regeneration mediated by
MAPK [52]. GH can also induce the phosphorylation of
IRS [53]. GH appears to facilitate tyrosine phosphorylation
of IRSs and build up their association with PI3K in a
variety of GH-responsive cells to full its function in
lipid and glucose metabolism [54–58]. Activation of the
GH/IRS/PI3K/Akt pathway is mediated by JAK2, and
there is no overt direct connection between the IRS
proteins and with the GHR [59].
Additionally, signal molecules in GH signalling
process like STAT, PI3K and MAPK do not serve for
GH merely; instead they are shared by many other
hormones. This is the basis for the interaction in the
cellular level between GH and other hormones especially
2 The effect of insulin on the pre-receptor
process: the effect on GH secretion and GH
level by insulin
In early stage of research, it is noticed that there is a
mutual effect of GH and insulin on each other secretion
inside mammalian bodies, including human beings.
Considering the inverse physiological function of these
two hormones, which mainly refers to the function of
regulating the lipogenesis and lipolysis, and the effect
on glucose metabolism, one may easily speculate the
inverse relationship between insulin and GH. With the
increasing incidence of diabetes, scholars have paid
more attention to the effect of GH on insulin in the past
ten years because GH influences insulin sensitivity.
Recent research has shown that the hyperinsulinemia
leads to the change in both GH secretion and GH level
in both diabetes condition and non-diabetes condition.
This finding has a significant meaning for endocrine
diseases or hormone disorders, and the effect of insulin
on GH secretion and GH level should be emphasized [9].
GH is stimulated by endogenous GHRH, which is
controlled by hypothalamus and stimulates the GH
stored in pituitary to be released to the blood circulation.
And it is inhibited by SRIF or SS. Importantly, SS
could reduce the release of GH from GH-releasing cells
(somatotropes) in pituitary, preventing excessive GH.
So, GHRH and SS regulate GH secretion together to
keep the normal concentration of GH in circulation [9, 21, 22].
In summary, GH secretion depends on three decisive
factors: GHRH released by hypothalamus, SS in the
body especially in the hypothalamus, and the GH cells
which store GH in pituitary.
2.1 The effect of insulin on GH secretion and GH
level under diabetes or non-diabetes condition
In a healthy body, insulin and glucagon are main fac-
tors for regulating glucose concentration. GH’s effect
on blood glucose is similar to glucagon, which acceler-
ates gluconeogenesis and restrains the absorption of
glucose from circulation to cells, so there is a balance
between GH and insulin on regulating glycol-metabo-
lism. However, in patients with diabetes, insulin is
relatively or absolutely in deficiency. The balance
between GH and insulin is disturbed, and it not only
imposes inuences on blood glucose, but can cause a
series of impacts on GH secretion and level.
As it is mentioned, to analyse the effect of insulin on
GH secretion, three elements should be considered:
GHRH, SS, and somatotropes. In 1985, Shibasaki and
colleagues found that pretreatment of insulin could
weaken the GH response to the administration of
GHRH-44, which suggests that insulin may cause the
desensitization of GHRH receptors in GH secretion
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
cells and enhance the level of SS [60]. Then in 1990,
scholars found the average GHRH levels were higher
in the control group than that of T1D subjects at all
stages after meals, while SS level had no difference [61].
Also, in T1D patients, the level of GH is higher, the
GHR level is lower than normal, and a raise in GH
secretion was observed following the reduction in insulin
level [10]. All these data suggest that a higher level of
insulin brings down the sensitivity of GHRH receptors
in somatotropes, which restrains the hypothalamus-
stimulated GH secretion. Meanwhile, insulin in normal
physiological concentration maintains the level and
sensitivity of GHR and GHRH action on somatotropes,
promoting the normal release of GH from pituitary.
When the blood glucose concentration is inuenced
by some pathological conditions, SS participates in the
effect of insulin on GH. Insulin-induced hypoglycaemia
can stimulate GH secretion mainly through inhibiting
hypothalamic SS release [62]. By contrast, when the
glucose concentration of blood is overloaded in diabetic
conditions, SS may be secreted in a greater level, and
reduce somatotrope-released GH. Insulin maintains the
balance with GH through SS. Even though one function
of SS is to restrict the glucagon, which is similar to
insulin, the overall effect of SS on glucose metabolism
does not completely accord with the level of insulin.
The further research on the interactive relationship
between the SS and insulin is needed.
In conclusion, insulin could maintain a balance with
GH in physiological conditions, which is essential for
glucose metabolism; but in diabetes, insulin may
reduce the sensitivity of GHRH receptor on somatotropes
and restrain GH secretion by increasing the level of SS.
GH could stay steady without changing with insulin’s
fluctuation because of self-regulation of GH. Insulin
regulates the secretion of SS and GH to better control
the blood glucose level. By realizing the relationship
among GH, insulin and their mediator SS, we may treat
diabetes from a new perspective, and better understand
how insulin-replacement therapy influences GH level
and secretion when treating diabetes. The mechanism
of insulin on GH may be different in T1D and T2D.
The matter about how the effect of insulin on GH
changes with different conditions of body and with
hormones’ concentrations need to be further studied. A
recent research in vitro has showed that somatotropes in
hypophysis possess many kinds of ion channels on their
membranes, especially Ca2+ channel, which is modied
by insulin, affects the signal transmission and then
exerts impact on the release of GH [19]. This is a possible
regulation mechanism of insulin in a sub-cellular level.
2.2 The effect of insulin on GH secretion and GH
level under obese or non-obese condition
Obesity is a complex medical condition caused by the
combination of many factors, one of which is disorder
of lipid metabolism [63]. Factors that can exert impacts
on lipogenesis or lipolysis lead to obesity. In mammal,
similar to glycometabolism, it is the balance between
GH and insulin that controls lipid metabolism. The
relationship between GH proles and obesity is proved
as enhanced obesity in patients lacking GH and in
animals, e.g. lit/lit mice, which cannot express GH [64].
Obesity is an important factor of decreased insulin
sensitivity and contributes to T2D. Therefore, obese
condition can influence both GH and insulin, and
influence the balance between them. The effect of
insulin on GH secretion and level under obese
condition also involves the effect of insulin on GHRH,
SS, and GH secreting cells.
De Schepper et al. found no overt relationship
between insulin and pulsatile GH secretion in both
obese and non-obese rats in an experiment of small
sample size, but the GH secretion was less and insulin
level was higher in obese group than that in non-obese
group [65]. This suggested that there were other factors
participating in the balance between GH and insulin. In
2001, Wang et al. found that insulin level was higher in
obese children compared with that in non-obese
children, and GH levels were remarkably lower in
obese boys [66]. When obesity occurs, the sensitivity of
insulin is lower, which brings hyperinsulinemia.
Increasing insulin stimulates SS secretion and inhibits
GH secretion. A study about children with obesity has
conrmed the idea that SS plays an essential role in the
connection between insulin and GH in obesity
condition. This study showed that, when chronic
increase appeared in SS secretion, pituitary-secreted
GH level would be reduced [67]. Sauter et al. considered
that insulin rstly stimulated the release of catecholamines,
and then catecholamines took a second step action to
promote the increase in SS [68]. In 2006, a study showed
that hypothalamus did not play an indispensable role in
regulating the secretion of GH. Unlike the regulation
pattern in diabetes mentioned above, the suppression of
GH in obesity condition is relatively independent of
GHRH and SS [69]. Insulin resistance may exist in the
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 547
somatotropes, just like it exists in many other cells [8].
Insulin signal in somatotropes is a result of systemic
regulation, and suppresses GH release directly. Insulin
can complete this effect even in systemic insulin
resistance individuals such as T2D patients, suggesting
a relatively sensitive status of somatotropes to insulin
in obesity [70, 71]. It also leads to a new question: obesity
impairs the insulin signaling, so logically the effect of
insulin on somatotropes in pituitary should also be
attenuated [72]. Why GH secretion and GH levels still be
suppressed by insulin-induced SS secretion? This
question is still open for further study. Gender is also a
crucial factor for the effect of insulin on GH. Androgen
may play an essential role in the difference [73].
Additionally, GH level in circulation is correlative
with the pulsatile secretion of GHRH, but it is not
absolutely depending on GHRH only. Cells expressing
GHR play a role in managing the GH levels. Insulin
treatment is found to enhance GH-induced JAK2 phos-
phorylation in accordance with the expression of
surface GHRs, but to decrease circulating GH, suggest-
ing that insulin may inuence GH level by inuencing
GHR sensitivity [74]. Interaction of GH with other hor-
mones on a cellular of molecular level also inuences
GH level, including a variety of signal proteins and
many pathways, which will be discussed below. Most
signicantly, GH level tends to be closely related to the
insulin level in circulation. Chen et al. have veried a
reverse effect of dietary-induced weight gain on insulin
and GH levels in circulation by discussing which
comes rst, obesity or the decline of GH [25]. Previous
studies tended to support the former. However, they
found the inhibition of pulsatile GH secretion coming
before dietary-induced weight gain (not obese yet), and
the level of GH, which showed the reverse relationship
with insulin, did not change parallelly with the circulat-
ing levels of NEFAs or glucose. Their result agreed
with Cornford’s study, which discovered that the
suppression of GH secretion and the improved insulin
sensitivity might be the reason for obesity, not the
result [11]. The clinical application is that we may pre-
vent or cure obesity by monitoring and regulating the
balance between GH and insulin.
In summary, the regulation of GH secretion by
insulin in people with obesity is different with the way
in people suffering diabetes. IR plays an important role
in inhibiting GH secretion in obese condition, while SS
and other hormones may mainly account for insulin-
induced decline of GH secretion in diabetes. During the
diet-induced weight gain, the regulatory effect of
insulin on GH may be stronger than the effect of GH
on insulin. For maintaining the safe lower levels of
NEFA and blood glucose, insulin level will increase
and cause suppression of GH secretion and decline of
GH level after calorie intake [25].
2.3 Mechanisms behind the effect of insulin on GH
According to the discussion above, hypothalamus is an
important site for insulin to exert inuence on GH,
especially in diabetes, with the participation of GHRH,
SS and other hormones in the body, all of which lead to
inhibition of GH secretion and a lower GH level.
Hypothalamus is not the only target for GH level to be
influenced by insulin in obesity. The mediation of SS
secretion centrally and peripherally, the direct action of
insulin binding to IR, is very important for the regulation
of GH secretion and level. In addition, IGF plays an
important role. Recently IGF-1 has been considered an
inhibitor of GH secretion, and the GH/IGF-1 system
accounts for the visceral adiposity [9, 24]. This may be on
account of that IGF-1 and insulin have hybrid receptors [29].
Insulin can bind with the IGF receptor. If the level of
insulin is excessive, the prole of plasma IGF-1 will go
up, due to the lack of available receptor. IGF-1 gives
negative feedback to the GHRH/GH/IGF-1 axis, result-
ing in the decline of GH level. Meanwhile, the expres-
sion of GHRH and SS gene has no signicant change
in dietary-induced obesity [75]. Somatotropes and IR
may be the targets for insulin to affect GH secretion
and level directly and indirectly. The body may
sacrifice normal weight in order to prevent normal
metabolism from hyperlipidemia. In other words, people
overeating and with hyperglycemia have to pay the
price -- the tendency to suffer obesity by restraining the
GH secretion and level in order to sustain the normal
lipid and glucose concentration. Also, according to
some in vitro studies, this mechanism should have
protected body from too much lipolysis, but it may easily
lose control due to the decline of the number of GHR
expressed in adipocytes in the obese [76, 77]. For the
regulation pattern of the whole process, see Fig. 2.
3 The post-GHR interaction between GH
and insulin: Influence of insulin on GH sig-
nalling and mechanism
The successful process of GH secretion and the mainte-
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
nance of GH level do not guarantee the successful per-
formance of GH. Insulin can exert effect on the post-
GHR process too. The insulin-induced impairment of
GH overall function may involve insulin’s inuence on
GH signalling inside cells. It is found that a physiologi-
cal dose of insulin is required for maintaining normal
liver GH signalling responsiveness both in vivo and in
vitro, and the lower fasting insulin was accompanied by
lower levels of GHR [6, 7, 78–80]. Crucial signal pathways
of GH have been already introduced above. Insulin has
different effect on these pathways, leading to the atten-
uation or enhancement of GH signalling. The interac-
tion between insulin and GH signalling is the basis for
understanding insulin’s effect on GH.
3.1 Shared signalling: the basis for the post-GHR
interaction between GH and insulin
Signalling of GH and insulin are not same in the receptor
level, but they partly begin to converge in the post-
GHR level. Decades ago, GH has shown the acute
insulin-like effect and chronic anti-insulin effect,
suggesting the shared signalling between the two hor-
mones [26, 81]. There are three main signal pathways as
mentioned above. GHR/JAK2/STATs and GHR/JAK2/
SHC/MAPK pathways mainly serve the function of
regulating the genes transcription for vital proteins
inside the nucleus, and GH/IRS/PI3K/Akt pathway
accounts for the regulation of lipometabolism and
glycometabolism. These pathways are shared between
GH and insulin for different purposes (see Fig. 3).
IR/IRS/PI3K/Akt is the vital pathway for insulin. It
has been found that this pathway participates most of
the cellular activities by insulin action such as glucose
transportation, glycogen synthesis, and suppression of
gluconeogenesis [82, 83]. Akt, a serine/threoine kinase, is
the most essential downstream molecule of PI3K. The
proteins in the downstream of Akt includes glycogen
synthase kinase-3 (GSK-3), BAD, forkhead box O1
(FoxO1) transcription factor. These effectors of Akt
have different destination, directly or indirectly affect-
ing the function of insulin signalling. Noticeably, GH
regulates metabolism of lipid and glucose through
PI3K/Akt pathway [82, 83], so insulin can interact or
cause crosstalk with GH in this pathway, through
Akt [84–86]. Moreover, PI3K is indispensable for the acti-
Fig. 2. The regulation pattern of GH proles in obesity. GH and insulin levels maintain a balance in body. They jointly control fat me-
tabolism and glucose metabolism. Overtaking calories leads to a high level of glucose and lipid in circulation, which will stimulate the
secretion of insulin and somatostatin. Also, a high level of blood lipid will tend to inhibit GH secretion. As insulin and somatostatin
increases, GH secretion decreases, so does its level in circulation. Moreover, GHR level decreases with its sensitivity being attenuated,
leading to the dysfunction of GHR and noneffective GH signaling. As a result of these actions, lipolysis is accelerated and lipogenesis
is restrained. In this condition, the concentrations of lipid and glucose can be controlled, although the weight gain increases. Abbrevia-
tions: GH, growth hormone; GHR, growth hormone receptor.
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 549
vation of MAPK [57, 87]. The signicance of PI3K/Akt to
both GH and insulin signalling is obvious.
MAPK pathway is also shared by GH and insulin. As
mitogen-activated protein kinase, MAPK plays a role
in promoting the growth, and has a minor role in
regulating the metabolism. PI3K and Ras-Raf-Mek-Erk
pathway are indispensable in stimulating the MAPK [83, 88].
Interestingly, MAPK has been shown to weaken the
signal of regulating metabolism emanated by insulin [89].
Fig. 3. Shared signal pathways between insulin and GH. GH signaling involves three signal pathways. The rst one mediated by
STATs proteins, which can activate SOCSs proteins, is shared by insulin with the particular participation of STAT5B. Insulin activates
SOCSs, which will block the combination of JAK2 and GHR. Also, SOCSs can attenuate the interaction between GHR and IRS. The
second way shared by insulin is mediated by SHC, a cytosolic protein. The engagement of SHC is responsible for the activation of
MAPK cascades. Insulin can enhance the tyrosine phosphorylation of IRS-1, which can facilitate MAPK activation. Insulin shows
an additive effect on GH-stimulated MAPK activation, by facilitating the activation of IRS. Another signal pathway of GH shared
by insulin is PI3K/Akt pathway. Tyrosine phosphorylation of IRS-1 and -2 leads to the activation of PI3K, a SH2 domain containing
protein, and its downstream Akt cascade. The activation of PI3K/Akt pathway is essential for the activation of other pathways, and
insulin coordinates GH’s insulin-like metabolic regulation in this pathway. Pathways mediated by STATs and MAPK are two major
pathways for the regulation of gene transcription, including genes of growth, metabolism and differentiation; PI3K/Akt pathway is
involved in activation of cytoplasmic targets and is important for metabolic regulation of GH and insulin, especially the regulation on
glucose and lipid in circulation. The shared signaling is the basis of the effect of insulin on GH signaling. Abbreviations: −, inhibition;
P, phosphotyrosine; GH, growth hormone; GHR, growth hormone receptor; INS, insulin; STAT, signal transducers and activators of
transcription; IRS, insulin receptor substrate; SOCSs, suppressors of cytokine signaling; SHC, src homology and collagen proteins;
MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B.
Since GH and insulin have reverse effect on the regula-
tion of glucose and lipid metabolism, MAPK may get
involved in the crosstalk between GH and insulin.
STAT pathway is a necessary pathway for GH to
regulate gene transcription for vital proteins, and it has
been elucidated that STAT5 is sensitive to pulsatile
secretion of GH [39]. According to Chen’s study in vitro,
STAT5b-Ct is phosphorylated by IR kinase domain
which was depurated. In the cells which overexpress
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
IR, STAT5b-Ct phosphorylation and overexpressed
endogenetic STAT5 were found [90]. Also, evidence
showed that SOCSs mRNA expression controlled by
insulin is also mediated by STAT5 [91]. Insulin interacts
with many other hormones including GH, luteinizing
hormone (LH), leptin and prolactin (PRL) in a
STAT5-dependent way [29, 92–94]. JAK2 may play a part
in the phosphorylation of STAT5 [94]. However, Zovnic
et al. found that insulin could not stimulate the
phosphorylation of STAT5 in vitro, instead, GH could.
This study was veried in vivo [95]. Whether STAT5 can
be activated by the insulin depends on the types of cells
and tissues and the physiological condition. Nowadays,
most scholars support that STAT5 is a physiological
substrate of IR [90]. Therefore, interaction can be medi-
ated by STAT5, which is important downstream protein
for both insulin and GH signalling.
3.2 The effect of insulin on MAPK pathway of GH
An in vitro study found that GH and insulin both can
stimulate the maximum activation of MAPK pathway
in a time- and dose- dependent way [59]. Insulin co-treatment
with different concentrations of GH showed an additive
effect on GH-stimulated MAPK activation when GH
concentration was low (5 and 25 ng/mL). Insulin
pretreatment (200 nmol/L insulin was added to GH 20
min in advance) had no effect on GH-induced MAPK
activation [12]. However, in vivo study showed that insulin
did not enhance GH-induced MAPK, suggesting
that insulin might play a positive role in GH-induced
MAPK signalling when the concentration ratio of GH
to insulin was suitable. It is also considered that IRS-1
can facilitate GH-induced MAPK activation. In the
same study, the co-treatment of insulin and GH
enhanced the tyrosine phosphorylation of IRS-1, and
the GH-induced MAPK activation also rose. We consider
that pretreatment of insulin-induced IRS may have
already been recruited before the treatment of GH, so
no additive effect was observed.
Mek/Erk can be phosphorylated without the involve-
ment of JAK2, Ras, and Raf-1, instead, with the
enhanced cell membrane translocation of Mek1/2.
These ndings suggest that insulin is indispensable for
GH-induced Erk1/2 activation and provide us a possible
explanation for the mechanism of insulin’s additive
effect on GH-induced MAPK signalling [13]. For the
effect of insulin on the GH/MAPK pathway, the role of
insulin may be not only additive, but also irreplaceable
for sensitivity of membrane kinase.
3.3 The effect of insulin on JAK2/STAT5 pathway
of GH signalling
In 1999, Ji [7] found insulin impairs GH signalling by
affecting JAK2/STAT5 pathway in vitro. Continuous
high concentration insulin treatment inhibited GH binding
and the GHR level, as well as the phosphorylation of
JAK2 and STAT5B in a time-dependent way [7].
However, some studies showed that high levels of insulin
and insulin treatment can enhance GH-induced JAK2
phosphorylation in accordance with expression of
surface GHRs [74]. Zhang et al. found that insulin per se
cannot induce STAT5 activation, conicting with previous
studies [12, 36, 90, 96]; however, insulin did improve GH-
induced STAT5 tyrosine phosphorylation in 3T3-F442A
adipocytes, both time- and dose-dependently. This
result is consistent with the study from Xu et al. [13].
This additive-effect was more overt when given
pre-treatment of insulin, and conclusions were con-
rmed in vivo [12]. These experiments suggest that insu-
lin’s inuence on GH/GHR/JAK2/STAT5 is not mono-
directional or monotypical, but depends on conditions.
Normal concentration of insulin is a necessity of the
responsive of GH signalling by maintaining the level of
GHR and phosphorylation of proteins in JAK2/STAT5
pathway. However, insulin above suitable range causes
inhibition of GH signal transmission. In the future, we
need to nd the relationships between effect, time and
dose of insulin treatment, pre-treatment, or the co-treat-
ment with GH. Also, the applicability in the counterpart
of human still need to conrm [13, 74, 97]. A curve graph
which shows how GH signalling intensity changes with
time and dose of insulin treatment, as well as other
factors should be made. Related endocrine diseases can
be better understood, and more evidence can be provided
for clinical therapeutics.
3.4 The effect of insulin on PI3K/Akt pathway of
GH signalling
PI3K is the most important downstream binding protein
for IRS. The IRS/PI3K/Akt pathway is essential for
insulin to implement metabolic regulation function and
for activation of MAPK [57, 87]. There has been substantial
evidence suggesting that PI3K/Akt mediates crosstalk
between GH and insulin signalling [84, 86]. A research
showed that under sepsis, there was a GH-resistant
condition, but when the sepsis objects were treated with
insulin, GHR and IGF-1 were back to normal levels,
and GH-resistance was alleviated. It was also found
QIU Han et al.: Inuence of Insulin on GH Secretion, Level and Signaling 551
that when PI3K/Akt pathway was blocked, the allevia-
tion effect of insulin could not work anymore. This
research suggested that in the pathology condition, a
suitable range of insulin can help GH maintain normal
function in the cellular level by regulating the IRS/
PI3K/Akt pathway [98]. For GH, PI3K/Akt pathway is
used for metabolic regulation in an insulin-like way
and it plays a coordinate role with insulin. Therefore,
another effect of insulin on PI3K/Akt pathway mainly
refers to coordinating GH’s insulin-like metabolic
regulation, including accelerating the transportation of
blood glucose and amino acid into cells, down-regulating
the blood glucose level, and inhibiting the lipolysis. As
to the long-term effect of GH, namely, anti-insulin
effect, it may involve insulin’s effect on other pathways
of GH’s signalling.
3.5 Mechanisms of the effect on GH signalling by
In combination with previous experiment data, if insulin
is pretreated on GH system, inslin is more likely to
exert suppressive impact on the GH signalling when
the period of insulin pretreatment is relatively long.
This mechanism may involve SOCSs. Short period (less
than 1 h) of pretreatment can help GHR maintain higher
abundance, but with the time span increasing, the insulin
will activate the STAT/SOCS pathway. SOCSs are able
to restrain JAK2 activity, so long period of insulin
pretreatment can interfere with the GH-induced phos-
phorylation of downstream protein [12].
For the co-treatment, time and dose are important
factors. According to Zhang’s study [12], it is hypothe-
sized that the dose of GH is more decisive than the
dose of insulin. When insulin’s dose did not change, the
change of GH dose could sharply affect the intensity of
signal molecules’ phosphorylation; however, when the
dose of GH was xed, even the dose of insulin changed
in ten-fold level, it only had a little effect on the result.
Both GH and insulin has the ability to activate down-
stream proteins, but the ability of GH may prevail with-
in a certain range. Therefore, once GH takes control the
path, insulin cannot compete. This hypothesis also
explained why the pretreatment of insulin is more
effective than co-treatment of GH and insulin: pretreat-
ment of insulin can help itself to take prior control of
the pathway, which can offset its weaker ability.
Considering all the work done, there are other factors
that affect insulin’s inuence on GH signalling. Besides
time and dose of insulin’s and GH treatment (including
the ratio of dose and time), possible factors include the
schedule and order when adding reagents, the whole
circumstance and condition of experiment, types of cell
and tissue and creatures used, all of which should be
taken into consideration. Just as it is mentioned, there
are many hormones interacting with GH or insulin via
their shared signalling. The reason why in vivo study is
different from in vitro study is that in vivo study tends
to be affected by a mixed regulation from other hor-
mones, such as leptin and ghrelin [92, 99, 100]. GHR should
also be taken into consideration. In 2004, Rhoads et al.
found that insulin enhanced the richness of the GHR
both in liver and adipose tissue of peri-parturient dairy
cows without affecting JAK2 and STAT5 proteins. It
implied that insulin can exert impact on GH signalling
through GHR [97]. Excess insulin can impair the sensi-
tivity of GHR, while suitable range of insulin maintains
normal GHR level. GHR, IR and IGF-IR are concomi-
tant in the lipid raft, which offers a site for these mole-
cules to interact with each other, and this microcosmic
reciprocity may be the cornerstone of crosstalk between
signal pathways [101–103].
4 Conclusions
Increasing evidence implies that insulin can exert ac-
tions on every part when GH is performing its function.
A physiological dose of insulin is necessary for the
maintenance of the level and sensitivity of GHR and
the action of GHRH on somatotropes, while excessive
insulin restrains the hypothalamus-stimulated secretion
of GH by attenuating the sensitivity of GHRH recep-
tors on GH secretion cells. Insulin also exerts effect on
GH secretion by inuencing the level of blood glucose
concentration and SS, especially in diabetes. Insulin’s
action on GH level is related to GH secretion and GHR
sensitivity, as well as the condition of the body espe-
cially the obesity. Bodies with excess calories con-
sumption have a reverse relationship between GH and
insulin. Insulin implements this effect by regulating
lipolysis and lipogenesis. IGF also get involved in the
insulin’s effect on pre-receptor process of GH. In
future, we may explore other possible regulation
pattern or related factors besides hypothalamus and IR,
and nd out how insulin works on them.
GH signalling is also affected by insulin because they
share signal pathways in the post-GHR signalling.
Insulin affects GH signalling in a time- and dose-
dependent way, and multiple factors are involved in
Acta Physiologica Sinica, October 25, 2017, 69(5): 541–556
this process, including IRSs, SOCSs and the sensitivity
of GHR. Insulin can activate IRS, which facilitates
GH-induced MAPK pathway. Insulin also stimulates
the phosphorylation of STAT5, and then SOCSs, which
can restrain the function of JAK2 and GHR/STAT5
pathway, but the reason of a few conflicting results
from in vivo and in vitro studies needs further research.
Insulin helps GH maintain normal function by regulating
the IRS/PI3K/Akt pathway in the cellular level in the
pathological condition. This process may involve other
In future, we should focus on the details of factors
and genes responsible for the interaction between insulin
and GH in different conditions. More substantial
evidence is in need for diagnosis and therapies of
endocrine disorders in clinical medicine eld.
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... There are key signaling pathways via RAS/MEK/ERK and PI3K/AKT/mTOR that are activated following cellular activation of IGF1R, and mainly serve the function of regulating unrestricted cell proliferation and decreased sensitivity to apoptotic mechanisms that involve changes in glucose and lipid metabolism and protein synthesis in target tissues responsible for promoting growth, development, and maintenance at all physiological stages [38, 39,40]. AKT, a principal target of PI3K signaling for IGF1, regulates glucose metabolism (glucose transportation, glycogen synthesis and gluconeogenesis inhibition) via GSK3 phosphorylation/inhibition and mTOR activation [38, 40,41]. ...
... There are key signaling pathways via RAS/MEK/ERK and PI3K/AKT/mTOR that are activated following cellular activation of IGF1R, and mainly serve the function of regulating unrestricted cell proliferation and decreased sensitivity to apoptotic mechanisms that involve changes in glucose and lipid metabolism and protein synthesis in target tissues responsible for promoting growth, development, and maintenance at all physiological stages [38, 39,40]. AKT, a principal target of PI3K signaling for IGF1, regulates glucose metabolism (glucose transportation, glycogen synthesis and gluconeogenesis inhibition) via GSK3 phosphorylation/inhibition and mTOR activation [38, 40,41]. Increased phosphorylated levels of AKT, GSK3β and mTOR were speci cally found in the hypothalamus of Pappa2 ko/ko females, and this may suggest a close regulatory control of glucose metabolism and protein synthesis in the female hypothalamus. ...
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Background Patients with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations have progressive postnatal growth retardation and high circulating levels of IGF1 bound in ternary complexes. The present study aims to assess whether Pappa2 deficiency is associated with sex-specific differences in the main components of IGF1 ternary complexes and IGF1 signaling pathways in response to low IGF1 bioavailability. Methods Plasma, hypothalamus, pituitary gland and liver were analyzed in constitutive Pappa2ko/ko mice of both sexes that have reduced skeletal growth and impaired bone composition. Results The reduction in body and femur length of Pappa2ko/ko mice was associated with increases in total IGF1 and IGFBP5 concentrations in plasma of females, Igfbp5 mRNA levels in the hypothalamus of males, and Igf1, Igfbp3 and Igfals mRNA levels in the liver of females, suggesting sex- and tissue-specific effects of Pappa2 deficiency on IGF ternary/binary complexes. Pappa2 deficiency was also accompanied by increased pituitary GH concentrations in both sexes. Sex-specific dysregulation of IGF1 signaling pathways was found in Pappa2ko/ko mice with higher phosphorylated forms of AKT, mTOR, GSK3β and ERK1/2 in the female hypothalamus, GSK3β in the male pituitary gland, and PI3K and AMPKα in the female liver, suggesting sex-based alterations in regulators of cell proliferation/growth and protein/glucose metabolism. Conclusions These data suggest that sex-specific differences in IGF ternary complexes and IGF1 signaling pathways are associated with Pappa2 deficiency, pointing to molecular mechanisms that may participate in the physiopathology of postnatal growth retardation in a sex-dependent manner.
... Conversely, elevations in FFA levels have been found to inhibit GH secretion, both at baseline and in response to various stimuli, such as reductions in FFA levels, hypoglycemia, physical exercise, or administration of GHRH or GHRP-6 (a synthetic hexapeptide that specifically triggers the release of GH by pituitary somatotrophs) [75]. Additionally, excess adipose tissue may also lead to increased levels of circulating insulin and FFAs, inhibiting GH secretion [76]. ...
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Obesity is a growing public health problem worldwide, and GH and IGF-1 have been studied as potential therapeutic targets for managing this condition. This review article aims to provide a comprehensive view of the interplay between GH and IGF-1 and metabolism within the context of obesity. We conducted a systematic review of the literature that was published from 1993 to 2023, using MEDLINE, Embase, and Cochrane databases. We included studies that investigated the effects of GH and IGF-1 on adipose tissue metabolism, energy balance, and weight regulation in humans and animals. Our review highlights the physiological functions of GH and IGF-1 in adipose tissue metabolism, including lipolysis and adipogenesis. We also discuss the potential mechanisms underlying the effects of these hormones on energy balance, such as their influence on insulin sensitivity and appetite regulation. Additionally, we summarize the current evidence regarding the efficacy and safety of GH and IGF-1 as therapeutic targets for managing obesity, including in pharmacological interventions and hormone replacement therapy. Finally, we address the challenges and limitations of targeting GH and IGF-1 in obesity management.
... Because pituitary-derived GH was involved in cell growth and regeneration processes 37 and tied to metabolic changes, 40 we assessed the kinetics of growth hormone changes and noted that a delayed but concentration-dependent increase in GH occurred at 4 h Data show mean ± SE of the mean (n = 6-8 animals=group). One sample was removed from all analyses at time 4 h (0:4 ppm; no serum collected); subsequent samples prioritized until empty in the following order: ACTH = TSH = PRL = LH FSH = GH = FFA > Corticosterone > Epinephrine > Leptin > Insulin, resulting in sample sizes of 6 for leptin, insulin, epinephrine, corticosterone, and GH, and n = 8 for all other end points. ...
Background: Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones. Objectives: We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones. Methods: First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and 0.8 ppm) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists. Results: Ozone (0.8 ppm) was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4-6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists. Discussion: We demonstrated the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model. Stress hormones assessment with real-time glucose monitoring may be useful in identifying interactions among irritant pollutants and stress-related illnesses.
... GHD is along with severe hepatic steatosis, fibrosis, adipogenesis, and IR due to the lack of aforementioned genes (139). GH stimulates JAK2-STAT5 activation, promotes lipolysis and insulin sensitivity and attenuates lipogenesis (149). The activation of STAT-5b may inhibit the expression of downstream genes. ...
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Nonalcoholic fatty liver disease (NAFLD) has emerged as the most frequent chronic liver disease globally. NAFLD is strongly associated with metabolic syndrome and it has been recently suggested that to rename NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). NAFLD has been studied in different endocrine axes and accumulating body of clinical and experimental studies have suggested that NAFLD is associated with polycystic ovarian syndrome (PCOS), hypopituitarism, growth hormone deficiency (GHD), hypogonadism and other endocrine disorders. In fact, endocrine dysfunction may be considered as the major contributor for the development, progression, and severity of NAFLD. In the present comprehensive review, we discussed the epidemiological and clinical evidence on the epidemiology, pathophysiology, and management of NAFLD in endocrine disorders, with an emphasis on the effects of sex-specific hormones/conditions as well as molecular basis of NAFLD development in these endocrine diseases.
... The circulating concentrations of neither the gonadotrophins nor PRL or TSH were influenced by DPIN. The case of GH was intriguing since the rise of ghrelin, a GH secretagogue, and the drop of insulin that inhibits somatotroph release of GH (for review see [23][24][25]), might us expect a different profile of effects. However, experimental data in animal models suggest that DPIN might exert a potent insulin-mimetic action in the hypothalamus (acting on insulin receptor signaling cascade but not through a direct effect on insulin receptors) [12], and potentially in the somatotrophs, deregulating the hypothalamic control of GH via growth hormone release hormone (GHRH) and mimicking insulin on its direct inhibitory effect on pituitary GH secretion [24,25]. ...
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The present study characterizes the oral pharmacokinetics of D-Pinitol, a natural insulin mimetic inositol, in human healthy volunteers (14 males and 11 females). D-Pinitol absorption was studied in (a) subjects receiving a single oral dose of 15 mg/kg (n = 10), or (b) 5 mg/kg pure D-Pinitol (n = 6), and (c) subjects receiving D-Pinitol as part of carbohydrate-containing carob pods-derived syrup with a 3.2% D-Pinitol (Dose of 1600 mg/subject, n = 9). The volunteers received a randomly assigned single dose of either D-Pinitol or carob pod-derived syrup. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 1440 min after intake. Plasma concentration of D-Pinitol was measured and pharmacokinetic parameters obtained. The data indicate that when given alone, the oral absorption of D-Pinitol is dose-dependent and of extended duration, with a Tmax reached after almost 4 h, and a half-life greater than 5 h. When the source of D-Pinitol was a carob pods-derived syrup, Cmax was reduced to 40% of the expected based on the data of D-Pinitol alone, suggesting a reduced absorption probably because of competition with monosaccharide transport. In this group, Tmax was reached before that of D-Pinitol alone, but the estimated half-life remained the same. In the D-Pinitol groups, plasma concentrations of glucose, insulin, glucagon, ghrelin, free fatty acids, and pituitary hormones were additionally measured. A dose of 15 mg/kg of D-Pinitol did not affect glucose levels in healthy volunteers, but reduced insulin and increased glucagon and ghrelin concentrations. D-Pinitol did not increase other hormones known to enhance plasma glucose, such as cortisol or GH, which were surprisingly reduced after the ingestion of this inositol. Other pituitary hormones (gonadotropins, prolactin, and thyroid-stimulating hormone) were not affected after D-Pinitol ingestion. In a conclusion, D-Pinitol is absorbed through the oral route, having an extended half-life and displaying the pharmacological profile of an endocrine pancreas protector, a pharmacological activity of potential interest for the treatment or prevention of insulin resistance-associated conditions.
... Those molecules have a growth-stimulating effect on many cells, most notably on osteocytes and chondrocytes, which results in bone growth [40]. Growth hormone also plays a role in glucose metabolism by inducing glycogenolysis in the liver and stimulating endogenous insulin production from the pancreas [41]. In the adipose tissue, GH increases lipolysis and inhibits lipogenesis. ...
Nearly 30% of patients with lipid profile abnormalities suffer from secondary dyslipidaemias. Endocrine disorders are one of the most important causes of dyslipidaemia. Dyslipidaemia can be observed in the pathologies of a variety of endocrine glands, including the thyroid, the pituitary, the adrenals, and the gonads. The most common endocrinopathy causing dyslipidaemia is hypothyroidism. In this paper, we review the lipid profile alterations observed in endocrinopathies. We describe changes in classic lipid profile parameters, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. However, we also focus on the influence of endocrine disorders on relatively new cardiovascular markers such as apolipoprotein B, apolipoprotein A1, and lipoprotein(a). While almost all endocrinopathies cause detrimental changes to the lipid profile, hyperthyroidism seems to be a disorder in which lowering of such parameters as total cholesterol, low-density cholesterol, and triglycerides can be observed. Comprehensive screening for endocrine disorders should always be included in the differential diagnostic process of secondary causes of dyslipidaemia. Early detection and treatment of endocrinopathy have a considerable impact on a patient's health. Proper treatment of those disorders plays a crucial role in modifying the cardiovascular risk and improving the lipid profile of those patients. Even though lipid-lowering therapy is usually still needed, in some cases restoration of hormonal balance might be sufficient to normalize the lipid profile abnormalities.
... Insulin is a peptide hormone that has several effects on the metabolism of fats, proteins and carbohydrates [36]. Growth hormone receptor (GHR) sensitivity and the level of insulinlike growth factor 1 (IGF-1) can also be affected by insulin, consequently influencing the level of growth hormone [67]. The insulin resistance pathway has been previously reported to be associated with height and body-weight trait in humans [68]. ...
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As a companion and hunting dog, height, length, length to height ratio (LHR) and body-weight are the vital economic traits for Jindo dog. Human selection and targeted breeding have produced an extraordinary diversity in these traits. Therefore, the identification of causative markers, genes and pathways that help us to understand the genetic basis of this variability is essential for their selection purposes. Here, we performed a genome-wide association study (GWAS) combined with enrichment analysis on 757 dogs using 118,879 SNPs. The genomic heritability (h2) was 0.33 for height and 0.28 for weight trait in Jindo. At p-value < 5 × 10−5, ten, six, thirteen and eleven SNPs on different chromosomes were significantly associated with height, length, LHR and body-weight traits, respectively. Based on our results, HHIP, LCORL and NCAPG for height, IGFI and FGFR3 for length, DLK1 and EFEMP1 for LHR and PTPN2, IGFI and RASAL2 for weight can be the potential candidate genes because of the significant SNPs located in their intronic or upstream regions. The gene-set enrichment analysis highlighted here nine and seven overlapping significant (p < 0.05) gene ontology (GO) terms and pathways among traits. Interestingly, the highlighted pathways were related to hormone synthesis, secretion and signalling were generally involved in the metabolism, growth and development process. Our data provide an insight into the significant genes and pathways if verified further, which will have a significant effect on the breeding of the Jindo dog’s population.
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MicroRNAs (miRNAs) may play a crucial regulatory role in the process of muscle atrophy induced by high-altitude hypoxia and its amelioration through resistance training. However, research in this aspect is still lacking. Therefore, this study aimed to employ miRNA microarray analysis to investigate the expression profile of miRNAs in skeletal muscle from an animal model of hypoxia-induced muscle atrophy and resistance training aimed at mitigating muscle atrophy. The study utilized a simulated hypoxic environment (oxygen concentration at 11.2%) to induce muscle atrophy and established a rat model of resistance training using ladder climbing, with a total intervention period of 4 weeks. The miRNA expression profile revealed 9 differentially expressed miRNAs influenced by hypoxia (e.g., miR-341, miR-32-5p, miR-465-5p) and 14 differentially expressed miRNAs influenced by resistance training under hypoxic conditions (e.g., miR-338-5p, miR-203a-3p, miR-92b-3p) (∣Fold Change∣≥1.5, p༜0.05). The differentially expressed miRNAs were found to target genes involved in muscle protein synthesis and degradation (such as Utrn, mdm2, eIF4E), biological processes (such as negative regulation of transcription from RNA polymerase II promoter, regulation of transcription, DNA-dependent), and signaling pathways (such as Wnt signaling pathway, MAPK signaling pathway, ubiquitin-mediated proteolysis, mTOR signaling pathway). This study provides a foundation for understanding and further exploring the molecular mechanisms underlying hypoxia-induced muscle atrophy and the mitigation of atrophy through resistance training.
Nonalcoholic fatty liver disease (NAFLD) is a common chronic metabolic liver disease worldwide. It is closely related to diseases of the cardiovascular system and chronic kidney disease. It can also occur secondary to many other diseases. Current research shows that patients with hypopituitarism have a high risk of developing NAFLD. After the adenohypophysis is dominated by hypothalamic hormones, hormones are secreted to act on the corresponding tissues or organs. It is characterized by a decrease in the thyroid hormone, cortisol, and growth hormone levels. In this review, we analyzed the mechanisms related to NAFLD through thyroid secretion, growth hormone secretion, sex hormone, and prolactin axes in patients with hypopituitarism, which will provide information and a theoretical basis for clinical diagnosis and treatment.
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Background Stress-related neurobehavioral and metabolic disorders are associated with altered circulating adrenal-derived hormones and hyperglycemia. Temporal assessment of glucose and these hormones is critical for insights on an individual’s health. Objectives Here we use implantable-telemetry in rats to assess real-time changes in circulating glucose during and after exposure to the air pollutant ozone, and link responses to circulating neuroendocrine stress and metabolic hormones. We also proposed to compare rodent glucose and corticosterone (cortisol in humans) responses to humans exposed to ozone. Methods First, using a cross-over design, we monitored glucose levels during single or repeated ozone exposures (0.0, 0.2, 0.4 and 0.8-ppm) and non-exposure periods in male Wistar-Kyoto-rats implanted with glucose-telemeters. A second cohort of un-implanted rats was exposed to ozone (0.0, 0.4 or 0.8-ppm) for 30-min, 1-hour, 2-hour, or 4-hour with hormones measured immediately after exposure. Then we assessed glucose metabolism in sham and adrenalectomized rats with or without pharmacological interventions of adrenergic and glucocorticoid receptors. Finally, we assessed glucose and cortisol in serum samples form a clinical study involving exposure of human volunteers to air or 0.3 ppm ozone. Results Ozone (0.8-ppm) caused hyperglycemia and hypothermia beginning 90-min into exposure, with reversal of effects 4-6 hours post-exposure. Glucose monitoring during four daily 4-hour ozone exposures revealed duration of hyperglycemia, adaptation, and diurnal variations. Ozone-induced hyperglycemia was preceded by increased adrenocorticotropic hormone, corticosterone, and epinephrine, but depletion of thyroid-stimulating, prolactin, and luteinizing hormones. Hyperglycemia was inhibited in rats that are adrenalectomized and/or treated with glucocorticoid inhibitor. There was coherence among rats and humans in ozone-induced corticosterone/cortisol increases. Discussion We demonstrate for the first time the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced metabolic dysfunction as exposure occurs. Real-time glucose monitoring with stress hormones assessment may be useful in identifying interactions among pollutants and stress-related illnesses.
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There is substantial evidence that the growth hormone (GH)/insulin-like growth factor (IGF) system is involved in the pathophysiology of obesity. Both GH and IGF-I have direct effects on adipocyte proliferation and differentiation, and this system is involved in the cross-talk between adipose tissue, liver, and pituitary. Transgenic animal models have been of importance in identifying mechanisms underlying these interactions. It emerges that this system has key roles in visceral adiposity, and there is a rationale for targeting this system in the treatment of visceral obesity associated with GH deficiency, metabolic syndrome, and lipodystrophies. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.
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IRS proteins are cellular adaptor molecules that mediate many of the key metabolic actions of insulin. When tyrosine is phosphorylated by the activated insulin receptor, IRS proteins recruit downstream effectors, such as phosphoinositide 3-kinase and mitogen-activated protein kinase, in order to elicit cellular responses such as glucose uptake, lipid metabolism and cell proliferation. There are two main IRS proteins in humans (IRS1 and IRS2), both of which are widely expressed. Given their central role in the insulin signalling pathway, it is not surprising that male mice lacking Irs1 or Irs2 present with elevated blood glucose or type 2 diabetes, respectively. For reasons yet to be identified, female Irs2−/− mice do not develop type 2 diabetes. A number of organs are affected by complications of diabetes; macrovascular complications include stroke and coronary artery disease, while nephropathy, neuropathy and retinopathy fall into the category of microvascular complications. Given the serious consequences of these complications on patient morbidity and mortality, it is essential to identify the molecular pathogenesis underlying diabetic complications, with a view to improving therapeutic intervention and patient outcomes. A number of recently published papers have converged on the hypothesis that the loss of insulin signalling and IRS proteins is instrumental to the development and/or progression of diabetic complications. This review will summarise some highlights from the published work in which this hypothesis is discussed.
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This article reviews the main findings that emerged in the intervening years since the previous volume on hormonal control of growth in the section on the endocrine system of the Handbook of Physiology concerning the intra- and extrahypothalamic neuronal networks connecting growth hormone releasing hormone (GHRH) and somatostatin hypophysiotropic neurons and the integration between regulators of food intake/metabolism and GH release. Among these findings, the discovery of ghrelin still raises many unanswered questions. One important event was the application of deconvolution analysis to the pulsatile patterns of GH secretion in different mammalian species, including Man, according to gender, hormonal environment and ageing. Concerning this last phenomenon, a great body of evidence now supports the role of an attenuation of the GHRH/GH/Insulin-like growth factor-1 (IGF-1) axis in the control of mammalian aging. © 2016 American Physiological Society. Compr Physiol 6:687-735, 2016.
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Obesity is a major public health concern. This condition results from a constant and complex interplay between predisposing genes and environmental stimuli. Current attempts to manage obesity have been moderately effective and a better understanding of the etiology of obesity is required for the development of more successful and personalized prevention and treatment options. To that effect, mouse models have been an essential tool in expanding our understanding of obesity, due to the availability of their complete genome sequence, genetically identified and defined strains, various tools for genetic manipulation and the accessibility of target tissues for obesity that are not easily attainable from humans. Our knowledge of monogenic obesity in humans greatly benefited from the mouse obesity genetics field. Genes underlying highly penetrant forms of monogenic obesity are part of the leptin-melanocortin pathway in the hypothalamus. Recently, hypothesis-generating genome-wide association studies for polygenic obesity traits in humans have led to the identification of 119 common gene variants with modest effect, most of them having an unknown function. These discoveries have led to novel animal models and have illuminated new biologic pathways. Integrated mouse-human genetic approaches have firmly established new obesity candidate genes. Innovative strategies recently developed by scientists are described in this review to accelerate the identification of causal genes and deepen our understanding of obesity etiology. An exhaustive dissection of the molecular roots of obesity may ultimately help to tackle the growing obesity epidemic worldwide.
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Ghrelin and its synthetic analog hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase (JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration reduces glucose levels and increases insulin-producing beta cell number, and insulin secretion in pancreatectomized rats and in newborn rats treated with streptozotocin, suggesting a possible role of GHS in pancreatic regeneration. Therefore, the discovery of GHS has opened many new perspectives in endocrine, metabolic, and cardiovascular research areas, suggesting the possible therapeutic application in diabetes and diabetic complications especially diabetic cardiomyopathy. Here, we review the physiological roles of ghrelin and hexarelin in the protection and regeneration of beta cells and their roles in the regulation of insulin release, glucose, and fat metabolism and present their potential therapeutic effects in the treatment of diabetes and diabetic-associated heart diseases.
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Chronic growth hormone (GH) therapy has been shown to cause insulin resistance, but the mechanism remains unknown. PTEN, a tumor suppressor gene, is a major negative regulator of insulin signaling. In this study, we explored the effect of chronic GH on insulin signaling in the context of PTEN function. Balb/c healthy mice were given recombinant human or bovine GH intraperitoneally for 3 weeks. We found that phosphorylation of Akt was significantly decreased in chronic GH group and the expression of PTEN was significantly increased. We further examined this effect in the streptozotocin-induced Type I diabetic mouse model, in which endogenous insulin secretion was disrupted. Insulin/PI3K/Akt signaling was impaired. However, different from the observation in healthy mice, the expression of PTEN did not increase. Similarly, PTEN expression did not significantly increase in chronic GH-treated mice with hypoinsulinemia induced by prolonged fasting. We conducted in-vitro experiments in HepG2 cells to validate our in-vivo findings. Long-term exposure to GH caused similar resistance of insulin/PI3K/Akt signaling in HepG2 cells; and over-expression of PTEN enhanced the impairment of insulin signaling. On the other hand, disabling the PTEN gene by transfecting the mutant PTEN construct C124S or siPTEN, disrupted the chronic GH induced insulin resistance. Our data demonstrate that PTEN plays an important role in chronic-GH-induced insulin resistance. These findings may have implication in other pathological insulin resistance.
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Insulin resistance is one of the major contributing factors in the development of metabolic diseases. The mechanisms responsible for insulin resistance, however, remain poorly understood. Although numerous functions of the prolactin receptor (PRLR) have been identified, a direct effect on insulin sensitivity has not been previously described. The aim of our current study is to investigate this possibility and elucidate underlying mechanisms. Here we show that insulin sensitivity is improved or impaired in mice injected with adenovirus that over-express or knock down PRLR expression, respectively. Similar observations were obtained in in vitro studies. In addition, we discovered that the Signal Transducer and Activator of Transcription (STAT)5 pathway is required for regulating insulin sensitivity by PRLR. Moreover, we observed that PRLR expression is decreased or increased under insulin-resistant (db/db) or insulin-sensitive (leucine deprivation) conditions, respectively, and found that altering PRLR expression significantly reverses insulin sensitivity under both conditions. Finally, we found that PRLR expression levels are increased under leucine deprivation via a General Control Nonderepressible (GCN)2/mammalian Target of Rapamycin (mTOR)/ribosomal protein S6 Kinase-1 (S6K1)-dependent pathway. These results demonstrate a novel function for hepatic PRLR in the regulation of insulin sensitivity and provide important insights concerning the nutritional regulation of PRLR expression.
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Pathological changes associated with obesity are thought to contribute to growth hormone (GH) deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contribute to progressive weight gain, and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight, epididymal fat mass, circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs) and glucose. Data were obtained from male mice maintained on a standard or high fat diet. We confirm the suppression of pulsatile GH secretion following dietary induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain, and thus precedes the development of obesity. Moreover, data illustrates key interactions between GH secretion and circulating levels of insulin, and reflects the potential physiological role of GH in modulating insulin-induced lipogenesis throughout positive energy balance.
Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases diagnosed in childhood. Childhood and adolescent years are also the most important period for growth in height and acquisition of skeletal bone mineral density (BMD). The growth hormone (GH)/insulin like growth factor -1 (IGF-1) axis which regulates growth, is affected by T1DM, with studies showing increased GH and decreased IGF-1 levels in children with T1DM. There is conflicting data as to whether adolescents with TIDM are able to achieve their genetically-determined adult height. Furthermore, data support that adolescents with T1DM have decreased peak BMD, although the pathophysiology of which has not been completely defined. Various mechanisms have been proposed for the decrease in BMD including low osteocalcin levels, reflecting decreased bone formation; increased sclerostin, an inhibitor of bone anabolic pathways; and increased leptin, an adipocytokine which affects bone metabolism via central and peripheral mechanisms. Other factors implicated in the increased bone resorption in T1DM include upregulation of the osteoprotegerin/ receptor-activator of the nuclear factor-κB ligand pathway, elevated parathyroid hormone levels, and activation of other cytokines involved in chronic systemic inflammation. In this review, we summarize the clinical studies that address the alterations in the GH/IGF-I axis, linear growth velocity, and BMD in children and adolescents with T1DM; and we review the possible molecular mechanisms that may contribute to an attenuation of linear growth and to the reduction in the acquisition of peak bone mass in the child and adolescent with T1DM.
Growth hormone (GH) exerts a diverse array of physiological actions that includes prominent roles in growth and metabolism, with a major contribution via stimulating insulin-like growth factor-1 (IGF-1) synthesis. GH achieves its effects by influencing gene expression profiles, and Igf1 is a key transcriptional target of GH signaling in liver and other tissues. This review examines the mechanisms of GH-mediated gene regulation that begin with signal transduction pathways activated downstream of the GH receptor and continue with chromatin events at target genes, and additionally encompasses the topics of negative regulation and crosstalk with other cellular inputs. The transcription factor Stat5b is regarded as the major signaling pathway by which GH achieves its physiological effects, including in stimulating Igf1 gene transcription in liver. Recent studies exploring the mechanisms of how activated Stat5b accomplishes this are highlighted, which begin to characterize epigenetic features at regulatory domains of the Igf1 locus. Further research in this field offers promise to better understand the GH-IGF-1 axis in normal physiology and disease and identify strategies to manipulate the axis to improve human health.